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Experimental and Molecular Therapeutics 39: Biochemical Modulators and Combination Chemotherapy

Suppression of human pancreatic tumor growth in vivo by sulindac and a novel analog of parthenolide with improved bioavailability

Michele Yip-Schneider, Huangbing Wu, Matthew Ralstin, Peter Crooks, Harikrishna Nakshatri, Christopher Sweeney and C. Max Schmidt
Michele Yip-Schneider
Indiana University School of Medicine, Indianapolis, IN and University of Kentucky, Lexington, KY
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Huangbing Wu
Indiana University School of Medicine, Indianapolis, IN and University of Kentucky, Lexington, KY
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Matthew Ralstin
Indiana University School of Medicine, Indianapolis, IN and University of Kentucky, Lexington, KY
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Peter Crooks
Indiana University School of Medicine, Indianapolis, IN and University of Kentucky, Lexington, KY
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Harikrishna Nakshatri
Indiana University School of Medicine, Indianapolis, IN and University of Kentucky, Lexington, KY
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Christopher Sweeney
Indiana University School of Medicine, Indianapolis, IN and University of Kentucky, Lexington, KY
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C. Max Schmidt
Indiana University School of Medicine, Indianapolis, IN and University of Kentucky, Lexington, KY
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DOI:  Published May 2005
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Proc Amer Assoc Cancer Res, Volume 46, 2005

Abstract

4949

Background: Cancer of the exocrine pancreas is the fourth leading cause of cancer-related deaths in the United States. Novel chemotherapeutic and chemopreventive options are needed for this disease. Parthenolide, an inhibitor of nuclear factor-kappaB (NF-κB), and sulindac, a cyclooxygenase (COX) inhibitor, show complementary antiproliferative effects on pancreatic cancer cells in vitro. An analog of parthenolide, (LC-1), has recently been synthesized that is more bioavailable. The aim of the present study was to evaluate the efficacy of LC-1 and/or sulindac in a xenograft model of pancreatic cancer in vivo. Methods: Proliferation (MTT) and NF-κB DNA binding assays were performed in the human pancreatic cancer cell line PaCa-2 to determine whether parthenolide and LC-1 had equivalent activities in vitro. To determine the dose of sulindac for in vivo studies, the effect of sulindac on prostaglandin E2 (PGE2) levels was determined ex vivo by ELISA in xenografted BxPC-3 pancreatic tumors 20 hours following a single oral administration of sulindac. For in vivo studies, nude mice were injected with BxPC-3 (COX-2 positive) or PaCa-2 (COX-2 negative) human pancreatic cancer cells. Drug treatment was initiated on the day of injection. Mice were randomly divided into six treatment groups that included placebo, low/high dose LC-1 (10 or 20 mg/kg, 40 mg/kg), low/high dose sulindac (20 and 60mg/kg), and combination of low dose LC-1/sulindac. Tumor size was measured twice weekly. Mean tumor volumes for each treatment group were calculated. Results: Parthenolide and LC-1 demonstrated equivalent antiproliferative effects and suppression of NF-κB DNA binding activity in PaCa-2 cells; in addition, similar cooperative repression of cell growth was observed in combination with sulindac in vitro. In ex vivo studies, 20 hours after treatment with low dose (20mg/kg) and high dose (60mg/kg) sulindac, PGE2 levels (2.1 +/− 1.4 and 1.33 +/− 0.5 pg PGE2/ug total protein, respectively) were decreased relative to placebo (3.86 +/− 0.5 pg PGE2/ug). The in vivo trial showed that the combination of 20mg/kg LC-1 and 20mg/kg sulindac suppressed the growth of BxPC-3 (COX-2 positive) xenografted tumors relative to placebo (P<0.05, t-test). Sulindac (60mg/kg) alone at earlier timepoints showed significant suppression of growth (P<0.05, t-test). LC-1 alone did not have any significant effect. In the PaCa-2 (COX-2 negative) xenografted tumors, the LC-1 and combination groups exhibited no significant change in growth. Interestingly, sulindac (60mg/kg) alone at the higher dose inhibited tumor growth relative to placebo (P<0.05, t-test). Conclusions: The parthenolide analog LC-1 and sulindac in combination inhibit tumor growth effectively in a COX-2 positive pancreatic tumor. Sulindac alone at a higher dose suppresses growth of a COX-2 negative pancreatic tumor, likely through a COX-independent mechanism.

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Cancer Research: 65 (9 Supplement)
May 2005
Volume 65, Issue 9 Supplement
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Suppression of human pancreatic tumor growth in vivo by sulindac and a novel analog of parthenolide with improved bioavailability
Michele Yip-Schneider, Huangbing Wu, Matthew Ralstin, Peter Crooks, Harikrishna Nakshatri, Christopher Sweeney and C. Max Schmidt
Cancer Res May 1 2005 (65) (9 Supplement) 1168-1169;

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Suppression of human pancreatic tumor growth in vivo by sulindac and a novel analog of parthenolide with improved bioavailability
Michele Yip-Schneider, Huangbing Wu, Matthew Ralstin, Peter Crooks, Harikrishna Nakshatri, Christopher Sweeney and C. Max Schmidt
Cancer Res May 1 2005 (65) (9 Supplement) 1168-1169;
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